A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells.

Effective antitumour immunity depends on the orchestration of potent T cell responses against malignancies1. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies2-4. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined. Here we demonstrate that a trispecific antibody to HER2, CD3 and CD28 stimulates regression of breast cancers in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumour cell cycle progression. Although CD8 T cells directly mediated tumour lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression at G1/S. Furthermore, when T cell subsets were adoptively transferred into a humanized breast cancer tumour mouse model, CD4 T cells alone inhibited HER2+ breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumour cell cycle progression and proliferation, and also increased pro-inflammatory signalling pathways. Collectively, the trispecific antibody to HER2 induced T cell-dependent tumour regression through direct antitumour and indirect pro-inflammatory/immune effects driven by CD4 T cells.

PREVALENCE OF VALVULAR REGURGITATIONS IN CLINICALLY HEALTHY CAPTIVE LEOPARDS AND CHEETAHS: A PROSPECTIVE STUDY FROM THE WILDLIFE CARDIOLOGY (WLC) GROUP (2008-2013).

The purpose of this prospective study was to evaluate transthoracic echocardiograms from clinically healthy large felids for the presence of valvular regurgitations (VR). Physiologic VR commonly occur in normal dogs and cats, but the percentage of large felids with VR has not been previously reported. During a 5-yr study period (2008-2013), 28 healthy animals were evaluated under general anesthesia: 16 cheetahs (Acinonyx jubatus soemmeringuii) with a mean age of 1.5±0.8 yr (range 0.7-3.5 yr), 5 Amur leopards (Panthera pardus orientalis), 1 snow leopard (Uncia uncia), and 6 clouded leopards (Neofelis nebulosa). For this study, all the leopards were gathered in one so-called "leopards group" with a mean age of 2.8±3.4 yr (range 0.3-10.7 yr). All valves observed in each view were examined for evidence of regurgitant jets and turbulent blood flow using the color-flow Doppler mode. Valves were also examined for structural changes. Mitral valve and aortic cusp abnormalities were considered to be of congenital origin. Mitral valve lesions led to mitral insufficiency in all the felids. Aortic cusp abnormalities led to aortic regurgitation in 94% of the cheetahs and 67% of the leopards. Leopards showed a predominance of early systolic mitral regurgitations, whereas all the mitral regurgitation jets in cheetahs were holosystolic. Tricuspid regurgitation was found in 81% of the cheetahs and in 50% of the leopards, whereas pulmonic regurgitation was detected in 44% of the cheetahs and 33% of the leopards. Interestingly, none of these tricuspid and pulmonic regurgitations were associated with two-dimensional structural valve abnormalities, thus suggesting their physiologic origin, as described in humans, cats, and dogs. In conclusion, subclinical valvular diseases are common in apparently healthy leopards and cheetahs. Longitudinal follow-up of affected animals is therefore required to assess their clinical outcome.